The preparation of pharmaceutical compositions capable of ensuring a gradual and controlled release of active ingredients included therein has long been known to the pharmaceutical art. Known systems include tablets, capsules, microcapsules, microspheres and other dosage forms where the active ingredient is released gradually by various mechanisms.
These systems are intended to provide pharmaceutical dosage forms that can prolong the presence of the active ingredients in the subject to which they are administered at optimum plasma levels, thereby reducing the number of administrations required and improving patients' response to treatment.
It was recently observed that some drug bioavailability problems could be overcome by prolonging the presence of dosage forms at or near the locus within the host where their active ingredients are normally absorbed. These bioavailability problems stem from causes such as limited drug solubility (gastric or enteral), small absorption rate constant, or the presence of "windows" of absorption on ( i.e. a limited time of absorption which stops upon saturation). Examples of such drugs (without limitation) include (i) carbamazepine (an antiepileptic), furosemide (a diuretic), metoprolol (a beta blocker) and acyclovir (an antiviral). Other drugs for which benefit from prolonged presence at or near the locus of absorption in terms of their bioavailability characteristics include drugs that act specifically on the gastrointestinal tract (e.g. 5-aminosalyc acid) or which are absorbed most efficiently within the colon (e.g. peptides or proteins such as insulin, interferon, calcitonin, endorphins, human growth hormone, and various hormone growth factors).
From a theoretical point of view, an ideal solution of this problem can be found in formulation or dosage form materials with bioadhesive characteristics, bioadhesiveness being defined as the ability of a material (synthetic or biologic) to adhere to biologic tissues for a prolonged period of time. Although the length of this time cannot be given in terms of a numerical range that would apply to all drugs and all routes of administration, it is fair to describe such prolonged time period as a period of time (i) during which a drug is present at or near the locus of its absorption (ii) which is longer than the standard residence time for such drug (usually) not exceeding 8-10 hours for the gastrointestinal tract and up to about 24 hours).
In case of oral administration, normal or pathological stomach voiding and intestinal peristaltic movements may reduce the time for which a drug-releasing dosage form remains in contact with the mucous membrane responsible for absorption of the active ingredient. The rectal route of administration profits from the presence of the dosage form in the lower section of the rectum, where rectal veins make it possible to by-pass (and thereby overcome the effect of metabolism on the first passage through) the liver. Similar considerations apply to the ocular, vaginal, dental and nasal cavities, where spontaneous or ciliary movements may cause a premature elimination of a dosage form. The purpose of the bioadhesive is, therefore, to keep a pharmaceutical dosage form in an absorption site for an extended period of time. Naturally, release of effective amounts of the active ingredient must also be ensured throughout the bioadhesion period in order to attain this objective.
Some examples of bioadhesive materials used in controlled release formulations are already known.
International Patent Application No. WO 85/02092 discloses a bioadhesive pharmaceutical composition containing bioadhesive agents for skin and mucous membrane administration. The bioadhesive agents are fibrous, cross-linked and water-swelling polymers bearing carboxyl functional groups, which are, however, not water-soluble. This composition may consist of various dosage forms such as an "intimate mixture" of active ingredient and bioadhesive polymers, capsules, films or laminates. However, by the simple physical mixing process described in WO 85/02092 the active ingredient is simply dispersed in a bioadhesive polymer and the dispersion is placed in a capsule. There is no real bond between each drug-containing particle or granule and the bioadhesive substance and thus the contact area between active ingredient/bioadhesive and mucosa is always less than optimal, which causes clustering or clumping of the drug particles and the loss of the advantages imparted by the bioadhesive.
Another example is European Patent No. EP 205,282, which discloses a pharmaceutical controlled-release composition containing cellulose the composition being capable of adhering to mucous membranes. This composition is a solid dosage form and is confined to administration via the oral or nasal cavities. It consists of granules coated with muco-adhesive cellulose. These granules contain a pharmaceutical active ingredient, a long-chain aliphatic alcohol and water-soluble hydrous hydroxyalkylcellulose, the latter being used both as a granule ingredient and as a extra-granular ingredient. In other words, the same polymer (cellulose) that is a significant constituent of the matrix responsible for release control is also the material relied upon for bioadhesiveness.
A third example is found in U.S. Pat. No. 4,226,848, which discloses an administration method for a bioadhesive pharmaceutical composition. This method is said to ensure adhesion to the oral or nasal cavities of a pharmaceutical composition which includes a bioadhesive polymer matrix in which the active ingredient is suspended. In this case, the bioadhesive matrix is made up of both a cellulose ether and an acrylic acid homopolymer or copolymer.
Most of the above examples are characterized by the fact that release is controlled by means of the same material which ensures bioadhesion. This implies that, if bioadhesion characteristics are adjusted (for example by increasing or decreasing the amount of the bioadhesive material in the drug formulation), the release characteristics peculiar to a formulation will also be unintentionally affected and the effect may be undesirable (for example it might cause the rate of drug release to be faster or slower than would be appropriate). It is instead desirable to be able to manipulate dosage form adhesion while maintaining the release profile of the active ingredient(s) typical of a selected formulation and to modulate the release system in relation to the active ingredient while maintaining unchanged the bioadhesive properties of a formulation.